Process for the manufacture of an aldehyde



Patented 06.19, 1948 PROCESS FOR 'rna MANUFACTURE OF AN ALDEHYDE HerbertLlndlar, Basel, Swltnerland, aslignor to floilmann-La Roche Inc.,Nntley, N. 1., a corporation of New Jersey No Drawing. Application JuneI, 1947, Serial No. 753,879. In Switaerland December 24, 1946 13 Chin.[Cl- 280-598) Ishikawa and Matsuura have described the manufacture of analdehyde CnHnO. 4-(2,6.B'- trimethyl cyclohexene (1') yl)-2-methyl-butene-(2)-al-(1) (IV) from fl-ionone (I) and a halogenoacetic ester (Chem. Zentralblatt 1937. II. 3452) Later on N. Milasreferred to the synthesis of this aldehyde (U. S. Patents Nos. 2,369,156and 2,369,160-16'7). Hellbron and coworkers proved (J. Chem. Soc. 1942.727; 1946, 502) that the aldehyde, contrary to prior statements,possesses a structure corresponding to formula IV, the double bond beingin the (1,5- position with respect to the carbonyl group. Heilbronstates the reaction to take the following course, "R in formula 11 beinglower alkyl, e. 3.,

"ethyl:

CH: CH:

omen-c o H=cn-c---on-c 001:

CH: CH:

Manage dn CH:

glyeldic mther 1 CH: CH:

CH: Gil-C O H- 0 0H CH JH:

glicidio acid CH: CH:

aldehyde CMHaO blatt 1937, II, 3452) or the giycylic acid 111 wasisolated therefrom and it was subsequently tried to split oil carbondioxide by heating in the presence of copper powder (J. Chem. Soc. 1942,727; 1946, 502) or by boiling with organic bases (U. 5. Patent No.2,369,160). All these processes lead with rather low yield to analdehyde CHHHO of low purity.

It was now found, according to the present invention, that the aldehyde014K230 4-(2',6'.6'- trimethyl cyclohexene (1') yl) -2-methyl-butene-(2)-al-(1) may be obtained with high yield in comparatively pure form bycondensing flionone with a halogeno acetic ester while avoidingapplication of high temperatures, treating the condensation productformed with alkali and isolating the aldehyde obtained from the reactionmixture.

For the preparation of the glycidic ester II fl-ionone may be condensedeither with a monoor with a di-halogeno acetic ester in a manner knownper se. The chloro compounds are especially suitable for this reaction.fi-Ionone and a mono halogeno acetic ester are reacted in the presenceoi an alkaline agent, such as an alkali alcoholate, an alkaline earthalcoholate or an alkali amide. Sodium alcoholate. preferably sodiummethylate, is an especially advantageous condensing agent. It isappropriate to carry out the reaction in the absence of a solvent, whileusing excess quantities of alcoholate and halogeno acetic ester.p-Ionone and di-halogeno acetic ester may be condensed in the usual waywith magnesium amalgam. The condensation product formed yields. ontreatment with an alkaline agent. the same reaction mass and the sameproducts II and IV. Equally the condensation of fl-ionone withmonohalogeno acetic ester may be eflect-ed with the aid of magnesiumamalgam. The condensation of p-ionone with halogeno acetic ester mustalways be carried out under mild conditions. It is advisable neither toisolate nor to purify the condensation product; it should especially notbe distilled. Preferably the condensation product is immediately treatedwith an alkaline agent. During the whole sequence of reactions thetemperature should not be allowed to rise above C. If these mild workingconditions are applied the deearboxylation of the glycidic acid III,which hitherto was only observed under acid conditions or on heating,occurs in alkaline milieu simultaneously with the hydrolysation. Thealdehyde formed may be isolated nearly quantitatively from the alkalinereaction solution. Distillation is well suited for the puriiication oithe product. It the above mentioned instructions are carefully followedthe aldehyde IV very high purity is obtained. I

The aldehyde thus obtained is a yellow oil which solidifies at about 40C. The properties thereof are identical with those oi the aldehyde whichHeilbron et al. (J. Chem. Soc. 1946, 502) obtained by the morecomplicated process from isolated glycylic acid and which they purifiedby preparing the crystalline phenylsemicarbazone. The aldehyde is wellcharacterized by its ultraviolet absorption spectrum having a distinctabsorption maximum at 230 p. The phenylsemicarbazone has its meltingpoint at 181-182 C. while the thiosemicarbazone melts at 194 C.(uncorrected).

The new process leads to a product of much higher purity. Furthermore,the yield is about four times higher than in the last mentioned knownprocess (J. Chem. Soc. 1946, 502). The whole process may now be executedin a single apparatus in the course oi! one day.

The term "alkaline agent" as employed in this disclosure and in theclaims is meant to define alkali agents and alkaline earth agents.

Example 1 20 parts by weight of p-ionone and 16 parts by weight 01'chloro acetic ethyl ester are stirred together intensively at an innertemperature of C. 9 parts by weight of pulverized dry sodium methylateare gradually added while excluding air and moisture; the temperature 0!the reaction mixture is kept at about 8 to 6 C. Alter completion of theaddition stirring and cooling is continued for 4 hours. 60 parts byvolume of a per cent. solution 01' sodium hydroxide in methanol are thenadded while cooling and stirring is continued for a Iurther 2 hours at+5 C. In order to isolate the aldehyde formed 90 parts of water areadded whereupon the mixture is subsequently extracted once with 40 partsby vol ume and twice with parts by volume 01 ether. The united etherextracts are twice extracted with 40 parts of water. Then the ether isdistilled of! and the residue is fractionated in high vacuo. Thefraction, boiling between 100 and 120 0., under a pressure oi 0.2mm./Hg. is redistilled and then boils, under 0.5 mm./I-Ig at IUD-102 C.18-19 parts by weight of the aidehyde are obtained which amounts to ayield of 85-90 per cent. of the theoretical. calculated for fl-ionone.

Example 2 20 parts by weight of fi-ionone, 16 parts by weight or chloroacetic ethyl ester and 20 parts by volume of petroleum ether of boilingpoint 30-70 C. are condensed by the aid of 8 parts by weight 01pulverized sodium methylate in the manner indicated in Example 1. Afterworking up 16.5-17.5 parts by weight of the aldehyde are obtained whichamounts to a yield of 75-80 per cent. (calculated for p-ionone).

Example 3 20 parts by weight of p-ionone, 16 parts by weight or chloroacetic ethyl ester are condensed by the aid of 8 parts by weight 01'sodium methylate in accordance with the indications in Example 1. Wateris added in a quantity amounting to four times the quantity of thereaction mass; the mixture is then extracted with ether. The ether isdriven oil in vacuo at a temperature below +20 C. 30-40 parts by weightof crude glycylic ester still containing some ether are obtained. Theproduct is treated with alcoholic alkali and the aldehyde formed isisolated from the alkaline reaction mixture (as indicated in Example 1).I

Example l 7 parts by weight 01 magnesium are dissolved under nitrogenatmosphere in 495 parts by weight of mercury while heating. Aftercooling down 300 parts by volume oi absolute ether, 55 parts by weightof fi-ionone and 45 parts by weight of chloro acetic ethyl ester areadded to the amalgam. The reaction is started by gentle warming and isthen kept going by stirring. For completion of the reaction i'urthergentle heating is necessary when the reaction shows signs of dying out.The magnesium compound formed is decomposed with water and dilute aceticacid. The mercury is removed and the reaction mixture is taken up inether. The ether solution is dried and then boiled down at a temperaturenot exceeding 40 C. 200 parts by volume of a 15 per cent. methylalcoholic solution of sodium hydroxide are slowly added to the residuewhile cooling. Alter the mixture has been left to stand for 2 hours fourtimes its quantity by volume of water are added. The solution isextracted with ether and the ether solution is washed with water. Theresidue obtained after driving oil the ether is fractionated in highvacuo. The small first running is discarded: the chief quantity distilsover at loo-.120? C. and is identical with the product obtainedaccording to Examples 1-3.

Example 5 7 parts by weight of magnesium are dissolved under nitrogenatmosphere in 495 parts by weight of mercury while heating. The amalgamis left to cool down whereupon 300 parts by volume of absolute ether, 55parts by weight of fl-ionone and 35 parts by weight of monochloro aceticethyl ester are added thereto. Further working is effected in accordancewith Example 4.

I claim:

1. Process for the manufacture of an aldehyde. comprising condensingp-ionone with chloro acetic ester in the presence oi sodium methylate,directly reacting the condensation product obtained with a methylalcoholic solution of sodium hydroxide, isolating the aldehyde formedfrom the part of the reaction mixture which is insoluble in aqueousalkali and keeping the temperature not above 50 0. throughout thereaction.

2. A process which comprises condensing :3- ionone with a halogenoacetic ester and reacting the condensation product with an alkalineagent to produce a compound of the formula:

C CH:

Hi 0 Bl said process being entirely carried out at a temperature not inexcess of 50 C.

3. A process according to claim 2 in which the ester is a monohalogenoacetic ester.

4. A process according to claim 2 in which the ester is a dihalogenoacetic ester.

5. A process according to claim 2 in which the condensing is carried outin the presence of an alkaline condensing agent.

6. A process according to claim 2 in which the condensing is carried outin the presence of map on nesium amalgam as a condensing agent.

'l. A process according to claim 2 in which the condensing is carriedout in the presence of alcar-OH CH0 kali alcoholate condensing agent. aon.

8. A process according to claim 2 in which the alkaline agent emplolyedto treat the condensa- 12. A process according to claim 11 in which tionproduct is an alcoholic solution oi an alkaline the alkaline m; isemployed 1n the form an agent alcoholic solution thereof.

9. A process according to claim 2 in which the 3, A process mordm t m 11m which alkaline Kent empmyed the treatment of the the alkaline agent isa: alcoholic solution of condensation product is a methanol solution oisodium m m sodium hydroxide. HERBERT LINDLAR.

10. A process according to claim 2 in which sodium methylate is employedas a condensing 15 REFERENCES CITED agent to assist in the initialreaction.

11. A process which comprises treating a comi g, g i g zf gg are ofrecord m the pound of the formula:

UNITED STATES PATENTS cm cm Number Name Date cn=cn-o-cn-coo (loweralkyl) 2.369.167 Milas Feb. 18, 1945 cm Bi OTHER. REFERENCES Heilbron etal.. Journal of the Chemical 80- with an alkaline agent at a temperaturenot in met? (Londim) 1943' Pages 7374733- excess of C. to produce thealdehyde 0! Cymerman 1-. Journal of the Chemical iormula: ciety (London)1946, pages 500-503.

Certificate of Correction Patent No. 2,451,740. October 19, 1948.

HERBERT LINDLAR It is hereby certified that errors appear in the printedspecification of the above numbered patent requiring correction asfollows:

Column 1, line 2, strike out the period after OuHgO and insert instead acomma; line 24, for "esther read ester; line 33, for glicidic readglyctdw; column 3, line 13, for the Greek letter s read m column 4, line13, for chloro read dwhloro; and that the said Letters Patent should beread with these corrections therein that an the same may conform to therecord of the case in the Patent Oflice.

Signed and sealed this 15th day of February, A. D. 1949.

THOMAS F. MURPHY,

Assistant Omnmiuianer of Patents.

condensing is carried out in the presence of map on nesium amalgam as acondensing agent.

'l. A process according to claim 2 in which the condensing is carriedout in the presence of alcar-OH CH0 kali alcoholate condensing agent. aon.

8. A process according to claim 2 in which the alkaline agent emplolyedto treat the condensa- 12. A process according to claim 11 in which tionproduct is an alcoholic solution oi an alkaline the alkaline m; isemployed 1n the form an agent alcoholic solution thereof.

9. A process according to claim 2 in which the 3, A process mordm t m 11m which alkaline Kent empmyed the treatment of the the alkaline agent isa: alcoholic solution of condensation product is a methanol solution oisodium m m sodium hydroxide. HERBERT LINDLAR.

10. A process according to claim 2 in which sodium methylate is employedas a condensing 15 REFERENCES CITED agent to assist in the initialreaction.

11. A process which comprises treating a comi g, g i g zf gg are ofrecord m the pound of the formula:

UNITED STATES PATENTS cm cm Number Name Date cn=cn-o-cn-coo (loweralkyl) 2.369.167 Milas Feb. 18, 1945 cm Bi OTHER. REFERENCES Heilbron etal.. Journal of the Chemical 80- with an alkaline agent at a temperaturenot in met? (Londim) 1943' Pages 7374733- excess of C. to produce thealdehyde 0! Cymerman 1-. Journal of the Chemical iormula: ciety (London)1946, pages 500-503.

Certificate of Correction Patent No. 2,451,740. October 19, 1948.

HERBERT LINDLAR It is hereby certified that errors appear in the printedspecification of the above numbered patent requiring correction asfollows:

Column 1, line 2, strike out the period after OuHgO and insert instead acomma; line 24, for "esther read ester; line 33, for glicidic readglyctdw; column 3, line 13, for the Greek letter s read m column 4, line13, for chloro read dwhloro; and that the said Letters Patent should beread with these corrections therein that an the same may conform to therecord of the case in the Patent Oflice.

Signed and sealed this 15th day of February, A. D. 1949.

THOMAS F. MURPHY,

Assistant Omnmiuianer of Patents.

